This invention relates to an improvement in one step of the multistep process of preparing penems from penams. More particularly, this invention relates to an improvement in the process step of cleaving the thiazolidine ring of a 6-substituted penicillanic acid ester and replacing the sulfur with an acyloxy or aroyloxy group, using an acyl nitrate or aroyl nitrate as the ring cleaving agent.
Penems are prepared by a multistep process from 6aminopenicillanic acid (6-APA). Thus, for example, 6-APA is converted to methyl (5R,6S,8R)-6-(1-hydroxyethyl)penicillanate by converting the 6-APA to (5R)-6,6-dibromopenicillanic acid with sodium bromide, esterifying the (5R)-6,6-dibromopenicillanic acid to the methyl ester with dimethylsulfate, introducing the (1-hydroxyethyl) substitutent to the 6-position with ethyl magnesium bromide and acetaldehyde then debrominating with zinc dust and ammonium chloride. The resulting methyl (5R,6S,8R)6-(1-hydroxyethyl)penicillinate can then be converted to a 4-acyloxy or aroyloxy azetidinone by cleaving the thiazolidine ring of the penicillinate.
U.S. Pat. No. 4,301,074 discloses one widely used method in which mercuric acetate is the cleaving agent. This method has the disadvantage of requiring a means to dispose of or recycle the mercury. Suaroto et al, Tetrahedron Letters No. 42, 4059-62 (1978) disclose a method in which the penicillinate is converted to the 1-oxide then cleaved with a carboxylic acid in the presence of trimethylphosphite. This method requires the use of the 1-oxide penam.
The 4-acyloxy or aroyloxy azetidinone which results from the known process is then converted by a series of steps, all of which are known in the art, to the desired penem.